The potential roles of osmotic and non-osmotic sodium handling in mediating effects of SGLT2 inhibitors on heart failure

Concomitant type 2 diabetes and chronic kidney disease (CKD) increases the risk of heart failure (HF). Recent STUDIES: demonstrate beneficial effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on CKD progression and HF hospitalization in patients with and without diabetes. In addition to inhibiting glucose reabsorption, SGLT2i reduce proximal tubular sodium reabsorption, possibly leading to transient natriuresis. We review the hypothesis that SGLT2i's natriuretic and osmotic diuretic effects mediate their cardio-protective effects. The degree to which these benefits are related to changes in sodium, independent of the kidney, is currently unknown. Aside from effects on osmotically active sodium, we explore the intriguing possibility that SGLT2i could also modulate non-osmotic sodium storage. This alternative hypothesis is based on emerging literature that challenges the traditional two-compartment model of sodium balance to provide support for a three-compartment model that includes the binding of sodium to glycosaminoglycans, such as those in muscles and skin. This recent research on non-osmotic sodium storage, as well as direct cardiac effects of SGLT2i, provides possibilities for other ways in which SGLT2i might mitigate HF risk. Overall, we review the effects of SGLT2i on sodium balance and sensitivity, cardiac tissue, interstitial fluid and plasma volume, and non-osmotic sodium storage

Partial least square regression applied to the QTLMAS 2010 dataset

Detection of genomic regions affecting traits is a goal in many genetic studies. Studies applying distinct methods for detection of these regions, called quantitative trait loci (QTL), have been described, ranging from single marker regression [1] to methods that enable to fit several markers simultaneously [2,3]. Simultaneously fitting all markers leads to more accurate detection of QTL compared to independent fitting of single markers in a regression model when there is linkage disequilibrium (LD) between the genomic regions that affect the trait but comes at the cost of increased computational requirements [2]. Partial least square regression (PLSR) is one method for simultaneously fitting multiple markers and was applied by Bjornstad et al. for detection of QTL [3]. An interesting characteristic of PLSR its straightforward application of to simultaneous analysis of data of multiple traits [3]. The objectives of this study were to use PLSR to search for QTL and to estimate breeding values in the dataset of the QTLMAS 2010 worksho

Succinate in dystrophic white matter: A proton magnetic resonance spectroscopy finding characteristic for complex II deficiency

A deficiency of succinate dehydrogenase is a rare cause of mitochondrial encephalomyopathy. Three patients, 2 sisters and I boy from an unrelated family, presented with symptoms and magnetic resonance imaging signs of leukoencephalopathy. Localized proton magnetic resonance spectroscopy indicated a prominent singlet at 2.40ppm in cerebral and cerebellar white matter not present in gray matter or basal ganglia. The signal was also elevated in cerebrospinal fluid and could be identified as originating from the two equivalent methylene groups of succinate. Subsequently, an isolated deficiency of complex II (succinate:ubiquinone oxidoreductase) was demonstrated in 2 patients in muscle and fibroblasts. One of the sisters died at the age of 18 months. Postmortem examination showed the neuropathological characteristics of Leigh syndrome. Her younger sister, now 12 months old, is also severely affected; the boy, now 6 years old, follows a Milder, fluctuating clinical course. Magnetic resonance spectroscopy provides a characteristic pattern in succinate dehydrogenase deficiency

M1 Resonances in Unstable Magic Nuclei

Within a microscopic approach which takes into account RPA configurations, the single-particle continuum and more complex $1p1h\otimes phonon$ configurations isoscalar and isovector M1 excitations for the unstable nuclei ${56,78}$Ni and ${100,132}$Sn are calculated. For comparison, the experimentally known M1 excitations in ${40}$Ca and $^{208}$Pb have also been calculated. In the latter nuclei good agreement in the centroid energy, the total transition strength and the resonance width is obtained. With the same parameters we predict the magnetic excitations for the unstable nuclei. The strength is sufficiently concentrated to be measurable in radioactive beam experiments. New features are found for the very neutron rich nucleus ${78}$Ni and the neutron deficient nucleus ${100}$Sn.Comment: 17 pages (LATEX), 12 figures (available from the authors), KFA-IKP(TH)-1993-0

Effects of Noise on Ecological Invasion Processes: Bacteriophage-mediated Competition in Bacteria

Pathogen-mediated competition, through which an invasive species carrying and transmitting a pathogen can be a superior competitor to a more vulnerable resident species, is one of the principle driving forces influencing biodiversity in nature. Using an experimental system of bacteriophage-mediated competition in bacterial populations and a deterministic model, we have shown in [Joo et al 2005] that the competitive advantage conferred by the phage depends only on the relative phage pathology and is independent of the initial phage concentration and other phage and host parameters such as the infection-causing contact rate, the spontaneous and infection-induced lysis rates, and the phage burst size. Here we investigate the effects of stochastic fluctuations on bacterial invasion facilitated by bacteriophage, and examine the validity of the deterministic approach. We use both numerical and analytical methods of stochastic processes to identify the source of noise and assess its magnitude. We show that the conclusions obtained from the deterministic model are robust against stochastic fluctuations, yet deviations become prominently large when the phage are more pathological to the invading bacterial strain.Comment: 39 pages, 7 figure

Large-scale synchrony of gap dynamics and the distribution of understory tree species in maple-beech forests

Large-scale synchronous variations in community dynamics are well documented for a vast array of organisms, but are considerably less understood for forest trees. Because of temporal variations in canopy gap dynamics, forest communities—even old-growth ones—are never at equilibrium at the stand scale. This paucity of equilibrium may also be true at the regional scale. Our objectives were to determine (1) if nonequilibrium dynamics caused by temporal variations in the formation of canopy gaps are regionally synchronized, and (2) if spatiotemporal variations in canopy gap formation aVect the relative abundance of tree species in the understory. We examined these questions by analyzing variations in the suppression and release history of Acer saccharum Marsh. and Fagus grandifolia Ehrh. from 481 growth series of understory saplings taken from 34 mature stands. We observed that (1) the proportion of stems in release as a function of time exhibited a U-shaped pattern over the last 35 years, with the lowest levels occurring during 1975–1985, and that (2) the response to this in terms of species composition was that A. saccharum became more abundant at sites that had the highest proportion of stems in release during 1975–1985. We concluded that the understory dynamics, typically thought of as a stand-scale process, may be regionally synchronized

Emerging Infectious Disease leads to Rapid Population Decline of Common British Birds

Emerging infectious diseases are increasingly cited as threats to wildlife, livestock and humans alike. They can threaten geographically isolated or critically endangered wildlife populations; however, relatively few studies have clearly demonstrated the extent to which emerging diseases can impact populations of common wildlife species. Here, we report the impact of an emerging protozoal disease on British populations of greenfinch Carduelis chloris and chaffinch Fringilla coelebs, two of the most common birds in Britain. Morphological and molecular analyses showed this to be due to Trichomonas gallinae. Trichomonosis emerged as a novel fatal disease of finches in Britain in 2005 and rapidly became epidemic within greenfinch, and to a lesser extent chaffinch, populations in 2006. By 2007, breeding populations of greenfinches and chaffinches in the geographic region of highest disease incidence had decreased by 35% and 21% respectively, representing mortality in excess of half a million birds. In contrast, declines were less pronounced or absent in these species in regions where the disease was found in intermediate or low incidence. Also, populations of dunnock Prunella modularis, which similarly feeds in gardens, but in which T. gallinae was rarely recorded, did not decline. This is the first trichomonosis epidemic reported in the scientific literature to negatively impact populations of free-ranging non-columbiform species, and such levels of mortality and decline due to an emerging infectious disease are unprecedented in British wild bird populations. This disease emergence event demonstrates the potential for a protozoan parasite to jump avian host taxonomic groups with dramatic effect over a short time period

Adaptive landscape genetics and malaria across divergent island bird populations

Environmental conditions play a major role in shaping the spatial distributions of pathogens, which in turn can drive local adaptation and divergence in host genetic diversity. Haemosporidians, such as Plasmodium (malaria), are a strong selective force, impacting survival and fitness of hosts, with geographic distributions largely determined by habitat suitability for their insect vectors. Here, we have tested whether patterns of fine‐scale local adaptation to malaria are replicated across discrete, ecologically differing island populations of Berthelot's pipits Anthus berthelotii . We sequenced TLR4, an innate immunity gene that is potentially under positive selection in Berthelot's pipits, and two SNPs previously identified as being associated with malaria infection in a genome‐wide association study (GWAS) in Berthelot's pipits in the Canary Islands. We determined the environmental predictors of malaria infection, using these to estimate variation in malaria risk on Porto Santo, and found some congruence with previously identified environmental risk factors on Tenerife. We also found a negative association between malaria infection and a TLR4 variant in Tenerife. In contrast, one of the GWAS SNPs showed an association with malaria risk in Porto Santo, but in the opposite direction to that found in the Canary Islands GWAS. Together, these findings suggest that disease‐driven local adaptation may be an important factor in shaping variation among island populations

Minimal Change Disease Is Associated With Endothelial Glycocalyx Degradation and Endothelial Activation

Minimal change disease (MCD) is considered a podocyte disorder triggered by unknown circulating factors. Here, we hypothesized that the endothelial cell (EC) is also involved in MCD

The Subcellular Distribution of Acyltransferases which Catalyze the Synthesis of Phosphoglycerides

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65213/1/j.1432-1033.1969.tb00602.x.pd